Table 2 Mechanisms by which EVs promote the shedding of tumor cells to form CTCs
From: The role of extracellular vesicles in circulating tumor cell-mediated distant metastasis
Main Process | Theory | EV cargo | Mechanism | Type of effect | Reference |
|---|---|---|---|---|---|
Epithelial-mesenchymal transition (EMT) | Carry the pro-EMT signaling factors | TGF-β1 | Act as an early signal to induce the phosphorylation of SMAD2 in A549 cells to regulate EMT | Directly | Yin et al. (2020) [139] |
| Â | Regulate key genes in the EMT pathway | lncUCA1 | Enhance EMT and activate metastasis through elevating Vimentin and MMP9 expression | Directly | Xue et al. (2017) [86] |
| Â | Â | miR-19b-3p | Upregulate the expression of N-calmodulin, Vimentin, and Twist, and downregulate E-calmodulin to promote EMT | Directly | Wang et al. (2019) [87] |
|  | Activate the Wnt pathway | miR-10527-5p | Affect EMT via Wnt/β-catenin signaling in vitro and in vivo | Directly | Xiao et al.(2023) [90] |
| Â | Activate the PTEN pathway | miR-19b-3p | Target the PTEN pathway to affect the expression of downstream EMT-related proteins | Directly | Zeng et al. (2020) [93] |
| Â | Â | miR-92a-3p | Promote EMT progression by inhibiting PTEN and activating the Akt/snail signaling pathway | Directly | Yang et al. (2020) [94] |
| Â | Promote macrophage M2 polarization | PKM2 | Induce M2 macrophage polarization via the AMPK pathway, thereby enhancing EMT | Indirectly | Zhou et al. (2022) [28] |
| Â | Â | miR-3591-3p | Promote macrophage M2 polarization by targeting the CBLB and activating JAK2/PI3K/Akt/mTOR and STAT3 pathways, thus promoting EMT | Indirectly | Li et al. (2022) [96] |
|  |  | miR-106b-5p | Promote macrophage polarization toward M2-like polarization by activating PI3Kγ/AKT/mTOR signaling pathway through downregulation of PDCD4 to activate macrophages promote EMT | Indirectly | Yang et al. (2021) [95] |
Extracellular matrix (ECM) remodeling | Carry ECM remodeling-related enzymes | MMP | \ | Directly | Tauro et al. (2013) [105] |
|  | Trigger fibroblast differentiation into CAFs | miR-425-5p | Activate the TGFβ1 signaling pathway by suppressing TGFβRII expression, thereby promoting the conversion of human breast fibroblasts (HMF) to the CAF phenotype | Indirectly | Zhu et al. (2022) [107] |
| Â | Â | lncRNA Gm26809 | Reprogram fibroblasts into tumor-promoting CAFs through transfer of lncRNA Gm26809 | Indirectly | Hu et al. (2019) [108] |
|  |  | miR-630 | Facilitate CAFs activation by inhibiting KLF6 and activating the NF-κB pathway | Indirectly | Cui et al. (2021) [109] |
|  | Facilitate the conversion of MSCs to CAFs | TGF-β | Trigger the differentiation of hucMSCs to CAFs through EVs-mediated TGF-β transfer and TGF-β/Smad pathway activation | Indirectly | Gu et al. (2012) [26] |
Angiogenesis | Promote angiogenesis | lncRNA ATB | Promote angiogenesis by regulating the miR-204-3p/TGFβR2 axis | Directly | Yuan et al. (2022) [114] |
| Â | Â | miR-30b-5p | Promote angiogenesis by inhibiting GJA1 | Directly | Chen et al. (2022) [115] |
| Â | Â | miR-663b | Inhibit the expression of adhesion protein (vinculin), thereby promoting angiogenesis | Directly | You et al. (2021) [116] |
| Â | Â | miR-183-5p | Promote angiogenesis through the regulation of FOXO1 | Directly | Shang et al. (2020) [140] |
| Â | Â | miR-221-3p | Promote angiogenesis by downregulating MAPK10 expression | Directly | Zhang et al. (2019) [117] |
| Â | Stimulate macrophages to release pro-angiogenic factors | miR-103a | Cause macrophages a high level of expression with pro-angiogenic factors VEGF and angiopoietin-1, thereby promoting angiogenesis | Indirectly | Hsu et al. (2018) [118] |
Vascular permeability | Target vascular endothelial -Cadherin (VE-Cad) | miR-27b-3p | Enhance vascular permeability by targeting VE-Cad and p120 | Directly | Dou et al. (2021) [123] |
| Â | Â | X26nt | Increase vascular permeability by binding VE-Cad in HUVECs | Directly | Chen et al. (2021) [126] |
| Â | Â | miR-939 | Target VE-Cad and lead to disruption of tight junctions | Directly | Di Modica et al. (2017) [127] |
| Â | Target the tightly linked component protein zonula occludens-1(ZO-1) | miR-455 | Increases vascular permeability by targeting ZO-1 | Directly | Xie et al. (2023) [129] |
| Â | Â | EphA2 | Enhance vascular permeability by downregulating ZO-1 and activate the RhoA pathway in endothelial cells | Directly | Liu et al. (2022) [31] |
| Â | miR-182-5p | Inhibit the tight junction-associated protein ZO-1, thereby enhancing vascular permeability | Directly | Li et al. (2020) [131] | |
| Â | miR-25-3p | Promote vascular permeability by targeting protein ZO-1 | Directly | Zeng et al. (2018) [132] | |
| Â | Â | miR-23a | Upregulate inhibition of tight junction protein ZO-1 to increase vascular permeability | Directly | Hsu et al. (2017) [133] |
| Â | miR-105 | Disrupt tight junctions by directly targeting protein ZO-1 | Directly | Zhou et al. (2014) [134] | |
Bind to the 3’UTR of the tight junction protein claudin-1 | miR-375-3p | Bind to the 3’UTR of the tight junction protein claudin-1 in vascular endothelial cells and negatively regulate its expression to disrupt the tight junctions | Directly | Mao et al. (2021) [135] | |
| Â | Target TIMP2/KLF2 | miR-3157-3p | Promote angiogenesis and increase vascular permeability by targeting TIMP2/KLF2 | Directly | Ma et al. (2021) [136] |